The proposed renewal project and others have shown that brain imaging can reveal abnormalities in regions critical for memory, the area of earliest deficit in AD, during preclinical stages. This is important because prevention strategies under development will likely need to be implemented at least 5-10 years prior to onset of dementia to be maximally effective. Patients with amnestic Mild Cognitive Impairment (MCI) have ~ 50% risk of developing AD within 4 years and are a key group for early intervention. During the initial project period, we enrolled, assessed and scanned a cohort of 50 patients with MCI, 50 euthymic older adults with marked cognitive complaints (CC) who function within normal limits on cognitive testing and 50 healthy controls (HC). Preliminary analyses show structural and functional changes in MCI patients in predicted brain regions (hippocampus and frontal cortex) and that these regions responded to cholinergic therapy. Genetic variation in several hypothesized pathways could partially explain the regional changes at baseline and the degree of medication response. Importantly, the CC group showed a strikingly similar pattern to the MCI group at baseline, suggesting the feasibility of identifying early imaging biomarkers predictive of high risk prior to cognitive decline. The goal of the renewal is to continue to follow the Dartmouth Memory and Aging Study cohort (at 3,4.5 and 6 years after baseline) in the context of an overarching model that structure, function and cognition during the preclinical stages of AD can best be understood in an integrative longitudinal framework viewed in relation to genetic vulnerability markers. The Specific Aims of the renewal are to determine: (I) clinical outcomes and antecedent predictors in the Dartmouth Memory and Aging Cohort including conversion/ progression rates and (II) regional neural mechanisms underlying longitudinal cognitive changes. Complementary 3T MRI measures will include morphometric indices of tissue integrity in key memory circuits, fMRI probes of episodic, working and semantic memory, and DTI / fMRI measures of connectivity. A supplemental aim represents a new research direction: (III) to examine the contribution of allelic variation in candidate gene pathways to individual differences in cognitive and neural trajectory and treatment response. This study will yield important new information on neuroimaging and genetic biomarkers for early detection prior to cognitive decline and for assessment of treatment response. [unreadable] [unreadable] [unreadable]